The transformation of normal cells within the body into cancerous and non-malignant neoplasms may be induced by viral infections, chemical carcinogens, radiation, physical agents or spontaneous tumorigenic growth. As a result of such transformation, normal cell surface antigen expression may be altered. New antigens--tumor specific antigens or antigens characteristic of premature cell types--or antigen expression pattern changes may be demonstrated on many tumor types. These antigenic changes are targets for the body's immune response.
In some instances, the extent or rate of cell transformation may exceed the capabilities of the body's immune response. Alternatively, the immune response may itself be ineffective or deficient. Supplemental methods have, therefore, been used in the treatment of transformed cells. These methods include non-surgical treatments, such as chemotherapy and radiation, and surgical treatments. Typically, these treatments are characterized by a range of undesirable side effects. Non-surgical treatments having immunosuppressant effects may increase the patient's susceptibility to secondary infections. Surgical treatments to excise transformed cells involve risks attendant with invasive procedures and may not effectively remove or eliminate the entire transformed cell population.
An alternative method of treatment for cancers and non-malignant tumors has involved the use of monoclonal antibodies to tumor specific antigens on the surface of transformed cells. The effectiveness of such treatments, typically involving murine monoclonal antibodies, is often limited by a variety of factors. For example, human patients treated with murine monoclonal antibodies may develop an anti-murine immunoglobulin response which severely reduces the effectiveness of further administration of murine monoclonal antibodies (G. E. Goodman et al., "Pilot Trial of Murine Monoclonal Antibodies In Patients With Advanced Melanoma", Journal Of Clinical Oncology, 3, pp. 340-51 (1985)). Other reported side effects of monoclonal antibody treatments include anaphylaxis, fever and chills.
Monoclonal antibodies are also ineffective in the treatment of those tumor specific surface antigens which modulate upon exposure to specific antibodies. Such antigens include, for example, the common acute lymphocytic leukemia antigen ("CALLA"), which appears on the surface of transformed cells of a majority of patients suffering from acute lymphocytic leukemia (J. Ritz et al., "Serotherapy Of Acute Lymphoblastic Leukemia With Monoclonal Antibody", Blood, 58, pp. 141-52 (1981)). When the CALLA antigen on the surface of a tumor cell is exposed to its specific antibody, the antigen migrates and the cell may internalize the antigen and antibody, preventing recognition of the tumor cell as a target by immune response effector cells such as leukocytes, lymphocytes, macrophages, killer ("K") cells or natural killer ("NK") cells.
In view of the disadvantages of such supplemental treatments, various therapies have been directed to augmenting the body's natural immune response to transformed cells. It is known that in the presence of antibodies, certain effector cells, such as lymphoid cells having surface bound receptors for the Fc regions of antibodies, mediate an antibody dependent cellular cytoxicity ("ADCC") reaction against target cells. By means of ADCC, these effector cells exert cytolytic activity against such target cells.
Two types of ADCC reactions have been demonstrated in vitro. In classical ADCC reactions, effector cells attach to antibody-coated target cells and subsequently cause cytolysis of the target cells (A. H. Greenberg et al., "Characteristics Of The Effector Cells Mediating Cytotoxicity Against Antibody-Coated Target Cells. I., Immunology, 21, p. 719 (1975)). This attachment between effector and target cell results from the interaction of the Fc region of the antibody coating the target cell and the Fc receptor of the effector cell. One disadvantage of this type of ADCC reaction is that it may be hampered by circulating antigen-antibody complexes, often associated with various diseases, which compete with the target-cell bound antibody for the Fc receptors of the effector cells (I. C. M. MacLennan, "Competition For Receptors For Immunoglobulin On Cytotoxic Lymphocytes", Clin. Exp. Immunol., 10, p. 275 (1972)). Due to this drawback of classical ADCC, a second type of ADCC reaction--antibody-directed ADCC--has been proposed. In antibody-directed ADCC, the target-specific antibody is first attached to the effector cell and the resulting complex is then "directed", via the antibody, to its specific antigen on the target cell surface. Advantageously, antibody-directed ADCC may not be affected by the presence of antigen-antibody complexes circulating in the host system.
The interaction between antibodies and effector cells via Fc region/Fc receptor attachment is normally weak. And, in some instances, antibodies do not remain associated with effector cells for a period of time sufficient to permit lysis of target cells. In view of this potential problem, antibodies have been attached to the effector cells using pretreatment with polyethylene glycol and a mixture of phthalate oils (J. F. Jones and D. M. Segal, "Antibody-Dependent Cell Mediated Cytolysis (ADCC) With Antibody-Coated Effectors: New Methods For Enhancing Antibody Binding And Cytolysis", J. Immunol., 125, pp. 926-33 (1980)). The applicability of this method for in vivo treatments, however, may be diminished by the toxic effects that any polyethylene glycol and phthalate oil residues on the antibody-effector cell complex may have on the body.
Alternatively, a method has been proposed for enhancing antibody-directed ADCC by adjuvant chemotherapy with cytotoxic drugs (I. R. Mackay et al., "Effect On Natural Killer And Antibody-Dependent Cellular Cytotoxicity Of Adjuvant Cytotoxic Chemotherapy Including Melphalan In Breast Cancer", Cancer Immunol. Immunother., 16, pp. 98-100 (1983)). Such a method, however, risks undesirable side effects resulting from the use of cytotoxic drugs.
Therefore, conventional means for treating cancer and non-malignant tumors by either supplementing or enhancing the body's immune response are characterized by various disadvantages. The need, thus, exists for an effective process and composition which avoid those disadvantages while providing effective treatment for cancers and non-malignant tumors.